Myelin-associated glycoprotein is a cell surface transmembrane molecule expressed on the surface of myelin consisting of five extracellular immunoglobulin domains, a single transmembrane domain and an intracellular domain. MAG expression is restricted to myelinating glia: oligodendrocytes in the central nervous system and Scwann cells in the peripheral nervous system. MAG interacts with neuronal receptor(s) which initiates bi-directional signalling between neurons and glia. The effect of MAG binding to neuronal receptors is known to result in inhibition of neurite outgrowth in vitro. Based on this in vitro data, antagonists of MAG have been postulated as useful for the promotion of axonal sprouting following injury (WO9522344, WO9701352 and WO9707810), although these claims are not supported by in vivo data. WO02/062383 discloses that an anti-MAG antibody, when administered directly into the brain or intravenously following focal cerebral ischaemia in the rat (a model of stroke) provides neuroprotection and enhances functional recovery.
Evidence in the literature suggests that MAG also mediates signalling intoglial cells, but the functional significance of this has not been understood. It has been reported that engagement of MAG expressed at the surface of a CHO cell using an antibody leads to the activation of fyn kinase (Umemori et al 1994, Nature, 367, 572-576). Furthermore, MAG knockout animals exhibit defects in myelin which resemble aspects of the defective changes observed in the brains of multiple sclerosis and encephalomyelitis patients (Lassman et al., Glia, 19, 104-110).
It has now been found that an anti-MAG monoclonal antibody previously shown to provide benefit in a rat model of stroke protects oligodendrocytes from oxidative-induced cell death in vitro. Furthermore, an increased number of histologically intact oligodendroctyes were observed in the brains of rats treated with anti-MAG compared to control antibody following middle-cerebral artery occlusion. Therefore anti-MAG antibodies (or MAG antagonists) may provide dual activities of promotion of neuronal regeneration as well as surprisingly triggering pathways which promote oligodendrocyte survival.
Oligodendrocyte damage or degeneration is observed in several neurological diseases including Alzheimer's disease (e.g. Roher et al, 2002, Biochemistry 41:11080-90; Xu et al, 2001, J. Neurosci. 2001 21:RC118), spinal cord injury (e.g. Crowe et al, 1997, Nature Medicine, 1997, 3:73-6; Beattie et al, 2002, Neuron 36:375-86), traumatic brain injury (e.g. Castejon et al, 2000, Brain Inj. 2000 April; 14(4):303-17) and multiple sclerosis. Therefore anti-MAG antibody or antagonists could provide benefit in these diseases in addition to stroke by both promoting neuronal regeneration and preventing oligodendrocyte cell death.